DESCRIPTION: Chronic pain and disability after war-related injuries, after trauma sustained in civilian settings and after surgery is unexpectedly common. Chronic pain related to traumatic brain injury (TBI) in combination with peripheral injuries is particularly problematic, and we have no well-validated treatments. Unfortunately, chronic pain after injuries also supports disability and cognitive impairment. Helping to explain this problem, observations in humans and animals suggest that central descending noradrenergic circuits and afferent neural pathways converge on the dorsal horn of the spinal cord to modulate sustained neuroplastic changes within specific populations of neurons. Furthermore, epigenetic mechanisms have emerged as a group of processes capable of integrating these intrinsic (e.g. descending pain modulation) and acquired (e.g. neural input from tissue disruption) factors into persistent changes in cellular functions. Such processes are activated by TBI and painful injuries. The neuroplasticity-related neurotrophin brain derived neurotrophic factor (BDNF) is a key part of spinal epigenetically-regulated pain sensitization. The main objective of this project is, therefore, to define the role of epigenetic mechanisms and their target genes in supporting pain and related changes after peripheral injury, particularly in the setting of TBI. In the first aim we evaluate the hypothesis that histoe acetyl transferase (HAT) inhibitors reduce pain, disability and cognitive dysfunction after soft tissue injury (incision), TBI and the combination of these injuries in a rodent model. A comprehensive group of outcome measures focused on nociception, spontaneous pain, functional (gait) abnormalities and cognitive (memory) changes will be used. Pharmacological treatments will include highly selective agents and drugs suitable for translational use. In the second aim we evaluate the hypothesis that HAT inhibitors block histone acetylation and the enhanced spinal expression of pain-related chemokine signaling molecules after peripheral injury, TBI and the combination of these injuries. We focus in this aim on the regulation of a key pain-related genes known to be epigenetically regulated, BDNF. The regulation of expression of this molecule through histone acetylation and the direct role of BDNF in pain and functional outcomes will be determined. In the third and final aim we will evaluate the role of changes in descending noradrenergic inhibition acting through the alpha-2 adrenergic receptor as a pathway linking TBI to the spinal neuroplastic changes under study. Again, selective agents suitable for use in humans will be used throughout this aim. At the time of completion of the project we expect to understand better how TBI, peripheral injury and the combination of injuries cause chronic pain. In the process of this evaluation we will delineate the roles of specific epigenetic mechanisms, gene targets and descending regulatory pathways in contributing to this very problematic form of chronic pain. We anticipate being in position to plan translational human studies.